Potential occupational carcinogen. NIOSH REL: TWA 0.03, IDLH:
60; OSHA PEL: TWA 0.3; ACGIH TLV: TWA 0.03.
LogP：
-0.9 at 20℃ and pH7
物理描述：
Acrylamide solution, [flammable liquid label] appears as a solution of a colorless crystalline solid. Flash point depends on the solvent but below 141°F. Less dense than water. Vapors heavier than air. Toxic oxides of nitrogen produced during combustion. Used for sewage and waste treatment, to make dyes and adhesives.
颜色/状态：
Flake-like crystals from benzene
气味：
Odorless
蒸汽密度：
2.45 (EPA, 1998) (Relative to Air)
蒸汽压力：
0.9 Pa (7X10-3 mm Hg) at 25 °C
亨利常数：
Henry's Law constant = 1.7X10-9 atm-cu m/mol at 25 °C (est)
Acrylamide is primarily (90 to 95%) excreted in the urine as conjugated metabolite with less then 2% parent compound appearing in the urine. Smaller amounts of metabolites are also present in feces, bile, and other biological matrices, still with only small amounts being eliminated as unchanged parent. Acrylamide elimination is biphasic with an alpha half-life of less than 5 hours and a beta half-life of 6 to 8 days.
Urinary metabolites among acrylamide-exposed animals were identified as N-acetyl-S- (3-amino-3-oxopropyl) cysteine (the N-acetyl-cysteine conjugate of acrylamide, following glutathione conjugation accounting for 67% of the total urinary metabolites found in rats, 41% of the total found in mice), N-acetyl-S- (3-amino-2-hydroxy-3-oxopropyl) cysteine (16% in rats, 21% in mice), N-acetyl-S- (1-carbamoyl-2-hydroxyethyl) cysteine (9% in rats, 12% in mice), glycidamide (6% in rats, 17% in mice), 2,3-dihydroxy-propionamide (2% in rats, 5% in mice), and a small amount of the parent compound (which was not possible to quantify).
... In the present study, a low-dose of acrylamide (ACR; 18 mg/kg) was administered to male Wistar rats for 40 days. Ultra performance liquid chromatography/time of flight mass spectrometry (UPLC-Q-TOF MS) was used to examine urine samples from ACR-dosed and control animals. Multiple statistical analyses with principal component analysis (PCA) were used to investigate metabolite profile changes in urine samples, and to screen for potential neurotoxicity biomarkers. PCA showed differences between the ACR-dosed and control groups 20 days after the start of dosing; a bigger separation between the two groups was seen after dosing for 40 days. Levels of 4-guanidinobutanoic acid and 2-oxoarginine were significantly higher in urine from the ACR-dosed group than in urine from the control group after 10 days (p<0.05). Receiver operator characteristic (ROC) curve analysis suggested that 4-guanidinobutanoic acid and 2-oxoarginine were the major metabolites. Our results suggest that high levels of 4-guanidinobutanoic acid and 2-oxoarginine may be related to ACR neurotoxicity. These metabolites could, therefore, act as sensitive biomarkers for ACR exposure and be useful for investigating toxic mechanisms. They may also provide a scientific foundation for assessing the effects of chronic low-dose ACR exposure on human health.
To study the toxic effect of chronic exposure to acrylamide (AA) at low-dose levels, we applied a metabolomics approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). A total of 40 male Wistar rats were randomly assigned to different groups: control, low-dose AA (0.2 mg/kg bw), middle-dose AA (1 mg/kg bw) and high-dose AA (5 mg/kg bw). The rats continuously received AA via drinking water for 16 weeks. Rat urine samples were collected at different time points for measurement of metabolomic profiles. Thirteen metabolites, including the biomarkers of AA exposure (AAMA, GAMA and iso-GAMA), were identified from the metabolomic profiles of rat urine. Compared with the control group, the treated groups showed significantly increased intensities of GAMA, AAMA, iso-GAMA, vinylacetylglycine, 1-salicylate glucuronide, PE (20:1(11Z)/14:0), cysteic acid, L-cysteine, p-cresol sulfate and 7-ketodeoxycholic acid, as well as decreased intensities of 3-acetamidobutanal, 2-indolecarboxylic acid and kynurenic acid in rat urine. Notably, three new candidate biomarkers (p-cresol sulfate, 7-ketodeoxycholic acid and 1-salicylate glucuronide) in rat urine exposed to AA have been found in this study. The results indicate exposure to AA disrupts the metabolism of lipids and amino acids, induces oxidative stress.
Acrylamide is absorbed following oral, inhalation, and dermal exposure and is widely distributed, tending to accumulate in the red blood cells. In the proposed major metabolic pathway acrylamide reacts with glutathione to form S-beta-propionamide glutathione conjugate which is excreted in the urine as cysteine or N-acetylcysteine derivatives. The major urinary metabolite (accounting for 48% of the excreted dose) is N-acetylcysteine-S-beta-propionamide. Alternately, acrylamide may be oxidized to glycidamide by CYP2E1. Glycidamide then goes on to form similar glutathione conjugates or undergos hydrolysis, leading to the formation of 2,3-dihydroxypropionamide and 2,3-dihydroxypropionicacid. (A635, A324, L1887)
IDENTIFICATION AND USE: Acrylamide is a white crystalline solid. Acrylamide is mainly used in the production of polymers and copolymers for various purposes. All acrylamide in the environment is man-made, the main source being the release of the monomer residues from polyacrylamide used in water treatment or in industry. HUMAN EXPOSURE AND TOXICITY: Acrylamide is toxic and an irritant. Cases of acrylamide poisoning show signs and symptoms of local effects due to irritation of the skin and mucous membranes and systemic effects due to the involvement of the central, peripheral, and autonomic nervous systems. Local irritation of the skin or mucous membranes is characterized by blistering and desquamation of the skin of the hands (palms) and feet (soles) combined with blueness of the hand and feet. Effects on the central nervous system are characterized by abnormal fatigue, sleepiness, memory difficulties, and dizziness. With severe poisoning, confusion, disorientation, and hallucinations occur. Truncal ataxia is a characteristic feature, sometimes combined with nystagmus and slurred speech. Excessive sweating in the limb extremities is a common observation. Sign of central nervous system and local skin involvement may precede peripheral neuropathy by as much as several weeks. Peripheral neuropathy can involve loss of tendon reflexes, impairment of vibration sense, loss of other sensation, and muscular wasting in peripheral parts of the extremities. Nerve biopsy shows loss of large diameter nerve fibers as well as regenerating fibers. Autonomic nervous system involvement is indicated by excessive sweating, peripheral vasodilation, and difficulties in micturition and defecation. After cessation of exposure to acrylamide, most cases recover, although the course of improvement is prolonged and can extend over months to years. There are no epidemiological data available on cancer due to exposure to acrylamide. There is no evidence in man of any teratogenic effects resulting from acrylamide exposure. ANIMAL STUDIES: In rats, biotransformation of acrylamide occurs through glutathione conjugation and through decarboxylation. At least 4 urinary metabolites have been found in rat urine, of which mercapturic acid and cysteine- S-propionamide have been identified. Acrylamide and its metabolites are accumulated (protein-bound) in both nervous system tissue and blood (hemoglobin-bound). Accumulation in the liver and kidney as well as the male reproductive system has also been demonstrated. In animal studies, early changes in visual-evoked potentials (VEP), preceding clinical signs, as well as changes in somatosensory-evoked potentials (SEP), have been seen. Degenerative changes have been described in peripheral nerve axons, with less severe changes in the longer fibers of the CNS. Degeneration of Purkinje cells has been observed in chronically-intoxicated animals. The changes are most pronounced in the nerve endings of myelinated sensory fibers. The nerve endings show enlarged "boutons terminaux" and a widespread enlargement of nerve terminals from the accumulation of neurofilaments. This occurs in both the peripheral and central nervous systems. Impairment of axonal transport has been found in sensory fibers, and interference with glycolysis and protein synthesis has been observed in biochemical studies. Studies of neurotransmitter distribution and receptor binding in the brains of rats have revealed changes induced by acrylamide. In rats, changes in the concentration of neurotransmitters and in striatal dopamine receptor binding have been related to behavioral changes. Degenerative changes in renal convoluted tubular epithelium and glomeruli and fatty generation and necrosis of the liver have been seen in monkeys given large doses of acrylamide. In rats, acrylamide disrupted the metabolism of lipids and amino acids, induced oxidative stress, impaired hepatic porphyrin metabolism. Acrylamide was not mutagenic in Salmonella typhimurium with or without metabolic activation. Acrylamide induced chromosomal aberrations in the spermatocytes of male mice and increased cell transformation frequency in Balb 3T3 cells with a metabolic activation. Acrylamide was shown to be an initiator for skin tumors in mice. It increased the incidence of lung tumors in mice-screening assays. Absorption of acrylamide by the fetus has been demonstrated in animal (pig, dog, rabbit, and rat) studies. Oral administration of acrylamide, between the 7-16th days of gestation in rats, decreased the binding of dopamine receptors in the striatal membranes in 2-week-old pups. Degeneration of seminiferous tubules and chromosome aberrations in spermatocytes has been seen in acrylamide-treated male mice. Depressed plasma levels of testosterone and prolactin have also been observed. A statistically-significant increase in the incidence of mesothelioma of the scrotal cavity was observed in rats after long-term (2-year) administration of acrylamide in the drinking-water. Administration over 2 years of acrylamide not only increased the incidence of a variety of tumor types (both benign and malignant) but also decreased the life expectancy in both male and female rats. ECOTOXICITY STUDIES: Acrylamide was genotoxic in C. auratus peripheral blood cells. The fish exposure also produced a dose-dependent increase in total DNA strand breakage, the formation of erythrocytic nuclear abnormalities and in the levels of hepatic cytochrome P4501A (CYP1A) and glutathione S-transferase (GST) activity. Acrylamide may induce gonadotoxicity in mussels.
Acrylamide produces a central-peripheral distal axonopathy when administered chronically. This is characterized functionally by decreases in the monosynaptic reflex and dorsal root potential and alterations in the characteristics of the dorsal root reflex. Acrylamide's neurotoxic effects may be caused by the disruption of fast axonal transport. Acrylamide is thought to bind to kinesin, which leads to impairment of the fast axonal transport system responsible for the distal delivery of macromolecules. This results in deficiencies in proteins responsible for maintaining axonal structure and function. Acrylamide may also disrupt nitric oxide signaling at nerve terminals by forming adducts with soft
nucleophilic sulfhydryl groups on cysteine residues.
In terms of reproductive toxicity, data suggest that acrylamide-induced male dominant lethal mutations may involve clastogenic events from binding of acrylamide and/or glycidamide to spermatid protamines or spindle fiber proteins and/or direct alkylation of DNA by glycidamide. Adverse effects on mounting, sperm motility, and intromission could also be related to distal axonopathy resulting from binding of acrylamide to motor proteins.
Acrylamide's mechanism of carcinogenicity is likely mutagenic, as the metabolite glycidamide is believed to react with proteins and DNA, causing mutations that persist in viable somatic cells and resulting in tumor formation. In addition, acrylamide's affinity for binding sulfhydryl groups on proteins could inactive proteins/enzymes involved in DNA repair and other critical cell functions. (A322, L1887, A2877)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
癌症分类：B2组可能的人类致癌物
Cancer Classification: Group B2 Probable Human Carcinogen
In accordance with the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005, 086237), acrylamide (AA) is characterized as "likely to be carcinogenic to humans." This characterization is based on the following findings: (1) chronic oral exposure of F344 rats to AA in drinking water induced statistically significant increased incidences of thyroid follicular cell tumors (adenomas and carcinomas combined in both sexes), scrotal sac mesotheliomas (males), and mammary gland fibroadenomas (females) in two bioassays; (2) oral, i.p., or dermal exposure to AA initiated skin tumors that were promoted by TPA in SENCAR and Swiss-ICR mice; (3) i.p. injections of AA induced lung adenomas in strain A/J mice. In addition, CNS tumors were found in both of the chronic F344 rat bioassays; and (4) ample evidence for the ability of AA (primarily associated with its metabolite GA) to induce a variety of genotoxic effects in mammalian cells.
Evaluation: There is inadequate evidence in humans for the carcinogenicity of acrylamide. There is sufficient evidence in experimental animals for the carcinogenicity of acrylamide. In making the overall evaluation, the Working Group took into consideration the following supporting evidence: (1) Acrylamide and its metabolite glycidamide form covalent adducts with DNA in mice and rats. (2) Acrylamide and glycidamide form covalent adducts with hemoglobin in exposed humans and rats. (3) Acrylamide induces gene mutations and chromosomal aberrations in germ cells of mice and chromosomal aberrations in germ cells of rats and forms covalent adducts with protamines in germ cells of mice in vivo. (4) Acrylamide induces chromosomal aberrations in somatic cells of rodents in vivo. (5) Acrylamide induces gene mutations and chromosomal aberrations in cultured cells in vitro. (6) Acrylamide induces cell transformation in mouse cell lines. Overall evaluation: Acrylamide is probably carcinogenic to humans (Group 2A).
Acrylamide is well absorbed after oral, dermal, inhalational, and parenteral exposure, including through intact skin and mucous membranes. Efficient absorption of this compound is demonstrated by the observation that peak blood concentrations occur at approximately 1 hour after exposure. It is estimated that human elimination rates of acrylamide are only one-fifth that seen in rats.
Acrylamide is primarily (90 to 95%) excreted in the urine as conjugated metabolite with less then 2% parent compound appearing in the urine. Smaller amounts of metabolites are also present in feces, bile, and other biological matrices, still with only small amounts being eliminated as unchanged parent. Acrylamide elimination is biphasic with an alpha half-life of less than 5 hours and a beta half-life of 6 to 8 days.
In rats given 0.5-100 mg/kg bw of either (1-14(C))- or (2,3-14(C))acrylamide intravenously or orally, radioactivity was distributed rapidly throughout the body, with no selective accumulation in any tissue. Radioactivity was also distributed evenly among tissues of beagle dogs and miniature pigs
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
...可以通过...粘膜和肺以及消化道吸收。
... Can be absorbed through ... mucous membranes and lungs as well as the GI tract.
通过Si-H活化Ph取代的[PSiP]钳子，合成了一种空气稳定的N杂环PSiP钳子氢化铁FeH（PMe 3）2（SiPh（NCH 2 PPh 2）2 C 6 H 4）（4）配体。制备了类似的强供电子i Pr取代[PSiP]钳形配体，并将其引入铁络合物中，得到铁氮络合物FeH（N 2）（PMe 3）（SiPh（NCH 2 P i Pr 2）2 C 6 H 4）（6）。都图4和图6显示了伯酰胺催化脱水成腈的相似的高效率。空气稳定的氢化铁4是稳定和方便制备的最佳催化剂。以中等至优异的产率获得了包括芳族和脂族物质在内的各种氰基化合物。提出了合理的催化反应机理。
[EN] AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION<br/>[FR] DÉGRONIMÈRES DE C3-GLUTARIMIDE LIÉS À UNE AMINE POUR LA DÉGRADATION DE PROTÉINES CIBLES
申请人：C4 THERAPEUTICS INC
公开号：WO2017197051A1
公开（公告）日：2017-11-16
This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.
An efficient and heterogeneous recyclable palladium catalyst for chemoselective conjugate reduction of α,β-unsaturated carbonyls in aqueous medium
作者：Dattatraya B. Bagal、Ziyauddin S. Qureshi、Kishor P. Dhake、Shoeb R. Khan、Bhalchandra M. Bhanage
DOI：10.1039/c1gc15050b
日期：——
An highly efficient PS-Pd-NHC catalytic system has been developed for chemoselective conjugate reduction of α,β-unsaturated carbonyl compounds providing good to excellent conversion with remarkable chemoselectivity (up to 100%). The developed protocol is more advantageous due to use of HCOONa as hydrogen source, environmentally benign water as solvent and effective catalyst recyclability.
Transition metal-free catalytic reduction of primary amides using an abnormal NHC based potassium complex: integrating nucleophilicity with Lewis acidic activation
作者：Mrinal Bhunia、Sumeet Ranjan Sahoo、Arpan Das、Jasimuddin Ahmed、Sreejyothi P.、Swadhin K. Mandal
DOI：10.1039/c9sc05953a
日期：——
potassium complex was used as a transitionmetal-free catalyst for reduction of primary amides to corresponding primary amines under ambient conditions. Only 2 mol% loading of the catalyst exhibits a broad substrate scope including aromatic, aliphatic and heterocyclic primary amides with excellent functional group tolerance. This method was applicable for reduction of chiral amides and utilized for the synthesis
Ruthenium-Catalyzed Oxidative Cross-Coupling Reaction of Activated Olefins with Vinyl Boronates for the Synthesis of (<i>E</i>,<i>E</i>)-1,3-Dienes
作者：Dattatraya H. Dethe、Nagabhushana C. Beeralingappa、Amar Uike
DOI：10.1021/acs.joc.0c02823
日期：2021.2.19
An oxidativecross-coupling reaction between activated olefins and vinyl boronate derivatives has been developed for the highly stereoselective construction of synthetically useful (E,E)-1,3-dienes. The highlight of this reaction is that exclusive stereoselectivity (only E,E-isomer) was achieved from a base-free, ligand-free, and mild catalytic condition with a less expensive [RuCl2(p-cymene)]2 catalyst
